Critical Reviews in Oral Biology and Medicine, 5(l):27-53 (1994)

Sex Steroid Hormones and Cell Dynamics

in the Periodontium
Angelo Mariotti, D.D.S., Ph.D.
Departments of Periodontology and Pharmacology and Therapeutics, Box 100434, J. Hillis Miller
Health Science Center, University of Florida, Gainesville, Florida 32610

ABSTRACT: The biological changes that occur in tissues of the periodontium during puberty, the menstrual
cycle, pregnancy, menopause, and oral contraceptive use have heightened interest in the relationship between sex
steroid hormones and periodontal health. These clinical observations coupled with tissue specificity of hormone
localization, identification of hormone receptors, as well as the metabolism of hormones have strongly suggested
that periodontal tissues are targets for androgens, estrogens, and progestins. The etiologies of periodontal
endocrinopathies are diverse; nonetheless, periodontal pathologies may be a consequence of the actions and
interactions of sex steroid hormones on specific cells found in the periodontium.

KEY WORDS: androgens, estrogens, progestins, periodontium, gingiva, epithelial cell, fibroblast, periodontal
diseases.

And take upon's the mystery of things, As if we were variety of hormones may be required to produce
God's spies. Shakespeare, King Lear, v, 3. a single, particular effect in a group of tissues. For
example, estrogens can function independently to
stimulate growth of the breast (promotion of fat
I. INTRODUCTION accumulation, connective tissue development, and
ductal growth), yet must work in concert with
Homeostasis of multicellular organisms is other hormones (prolactin, progesterone, placen-
contingent on communications between the endo- tal lactogen, glucocorticoids, thyroxine, and oxy-
crine, nervous, and immune systems. If any com- tocin) to regulate lactation. Because of the complex
ponent of this triad falters, the survival of the and diverse nature of hormones, it is difficult to
organism is at stake. Therefore, life is dependent arrange these chemical agents into discrete groups;
on a functioning endocrine system whose role is nonetheless, they can be categorized into two
to maintain the internal milieu of a multicellular classes according to their chemical structure. The
organism by using specific chemical messengers peptide/amino acid derivative hormones repre-
that recognize specialized macromolecules in sen- sent a large and diverse group of molecules that
sitive cells to transduce a signal into a distinctive range from complex polypeptides (luteinizing
response. hormone) to single amino acid derivatives (cat-
The central focus of endocrinology revolves echolamines). The other large hormone group
around specific regulatory molecules (i.e., hor- contains the steroid hormones. Steroid hormones
mones) that govern reproduction, growth and are derivatives of cholesterol and consist of a
development, maintenance of the internal envi- combination of three rings of six carbon atoms
ronment, as well as energy production, utiliza- each (phenanthrene) and one ring of five carbon
tion, and storage. As a result of these global atoms (cyclopentane) to form a complex hydro-
demands within the organism, it is not surprising genated cyclopentanoperhydrophenanthrene ring
that the actions of hormones are complex and system (see Figure 1). This group can be further
diverse in nature. A single hormone may elicit a divided into three principal sets: corticosteroid
different outcome in a variety of tissues or a hormones (glucocorticoids and mineralcorticoids),

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 sex steroid hormones in reproductive endocri-
nology, evidence has accrued that gonadal hor-
mones have a much broader role in human
tissues. Androgens, estrogens, and/or progestins
are now believed to be directly or indirectly
involved in the regulation of various, diverse
tissues such as the brain, heart, kidney, skin,
liver, and periodontium. Reports of the effects
of sex steroid hormones in the periodontium, a
FIGURE 1. Schematic diagram of the cyclopentano- unique structure composed of two fibrous (gin-
perhydrophenanthrene ring system. The three rings of giva and periodontal ligament) and two miner-
six carbons each and one ring of five carbon atoms are
alized (cementum and alveolar bone) tissues,
identified as A, B, C, and D rings.
have been noted for over a century. The effect
of sex steroid hormones on each periodontal
calcium-regulating steroid hormones (vitamin tissue has heightened interest in defining the
D and its metabolites), and gonadal or sex ste- specific relationship among androgens, estro-
roid hormones (estrogens, androgens, and gens, and progestins to normal function and
progestins) (see Table 1). disease in the periodontium.
The past 50 years have dramatically im- The goal of this article is to provide the reader
proved our perceptions concerning the actions with current information about the relationship
of sex steroid hormones in health and disease. between sex steroid hormones and cells of the
Although there is no doubt of the importance of periodontium. To accomplish this goal, three prin-

TABLE 1
The Chemical Formula and Sources of Secretion for the Principal Sex
Steroid Hormones
Hormone Principal Source Chemical Formula

Estradiol Ovary

Progesterone Ovary, Placenta

Testosterone Testis

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cipal areas are explored. First, a broad overview Progesterone
of steroid hormone physiology is considered. A
17a-Hydroxyprogesterone
general understanding of hormone transport, me-
tabolism, and mechanism of action provides the Androstenedione
background necessary for understanding hormone
Androstenediol •» Testosterone • • Estradiol
action in the periodontium. Second, the signifi- *
cance of sex steroid hormone effects in the Dihydrotestosterone
periodontium is reviewed. The reported clinical Androstanedione Androstanediol
phenomena observed during times of fluctuations
in hormone levels, the retention and metabolism
of sex steroid hormones, as well as the identifica- FIGURE 2. Biosynthesis and metabolism of testos-
tion of steroid receptors are important evidence terone.
for the periodontium being a target tissue for sex
steroid hormones. Finally, various theories of the
roles of steroid hormones in pathogenesis in the sex hormone-binding globulin (44% bound), as
periodontium are critically evaluated. An under- well as serum albumins and other proteins (54%
standing of the etiology of periodontal endo- bound) (Dunn etal, 1981). Secreted plasma an-
crinopathies is essential for the prevention and/or drogens are also metabolized to physiologically
treatment of sex steroid hormone-sensitive peri- weak or inactive molecules consisting of either
odontal diseases. 17-ketosteroids or polar compounds (diols, triols,
and conjugates) for excretion by the kidney or
II. SEX STEROID HORMONE liver (Kochakian and Arimasa, 1976).
PHYSIOLOGY The biological activities of androgens can be
observed in virtually every tissue of the body. The
A. Androgens more important functions of androgens include:
(1) male sexual differentiation of wolffian ducts,
All natural androgens are derived from a external genitalia, and brain in utero\ (2) develop-
19-carbon tetracyclic hydrocarbon nucleus known ment of adult male phenotype, including growth
as androstane. One of the most potent androgenic and maintenance of male sex accessory organs as
hormones, testosterone (17-hydroxy-androst-4-en- well as anabolic actions on skeletal muscle, bone,
3-one), is synthesized by the Leydig's cells of the and hair; (3) facilitation of human sexual behav-
testes, the thecal cells of the ovary and the adrenal ior, and (4) regulation of specific metabolic pro-
cortex. In men, testosterone is the principal plasma cesses in the liver, kidney, and salivary glands
androgen and is reduced to dihydrotestosterone (Mooradian et ai, 1987).
(17-hydroxy-5-androstan-3-one), the mediator of
most actions of the hormone (Mooradian etai, B. Estrogens
1987) (see Figure 2). The irreversible metabolic
conversion of testosterone to dihydrotestosterone The naturally occurring estrogens, estrone
(DHT) occurs only in tissues that contain the (3-hydroxyestra-1,3,5( 10)-triene-17-one), estra-
enzyme 5oc-reductase (Wilson, 1975). Testoster- diol (estra-l,3,5(10)-triene-3,17-diol), and estriol
one (but not DHT) can also be aromatized to (estra-l,3,5(10)-triene-3,16,17-triol), are charac-
estradiol by a number of extragonadal tissues (pri- terized by an aromatic A ring, a hydroxyl group at
marily adipose tissue and skeletal muscle), a com- C-3, and either hydroxyl groups (C-16 and C-17)
mon route of estrogen production in men. In or a ketone group (C-17) on the D ring. Estradiol
women, the major plasma androgen is androstene- is the most potent estrogen and is secreted by the
dione (androst-4-ene-3,17-dione), which can be ovary, testis, placenta, as well as by peripheral
secreted into the bloodstream or converted into tissues. Estrone is also secreted by the ovary;
either testosterone or estradiol by the ovary. Once however, the principal source in both women and
secreted into the bloodstream, the majority of men is through extragonadal conversion of
androgens are transported to their sites of action androstenedione in peripheral tissues (Siiteri and
by a hepatic-secreted carrier protein designated as MacDonald, 1973). In premenopausal women the

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most abundant physiological estrogen is estra- synthesized and secreted by the corpus luteum,
diol, and in men and postmenopausal women the the placenta, and the adrenal cortex. Similar to
most abundant estrogen in the plasma is estrone androgens, the vast majority of progesterone is
(Weinstein etal, 1974; Yen, 1977). Like other transported in the bloodstream by plasma pro-
lipid-soluble hormones, estrogens are transported teins; however, progesterone in the human is pri-
in the blood principally bound to carrier proteins; marily nonspecifically bound to globulin and
for example, estradiol in the plasma is bound by albumin proteins (MacDonald etal, 1991). The
either albumin (60%) or sex hormone-binding fate of plasma progesterone is dependent on he-
globulin (38%), leaving only 2% of the hormone patic, extrahepatic, and extraadrenal metabolism.
free (Wu etal, 1976). Both estradiol and estrone Both 5oc-dihydroprogesterone and deoxy-
are metabolized principally to estriol, which is the corticosterone (21-hydroxy-4-ene-3,20-dione) are
major estrogen detected in the urine (see Figure 3). the most probable active progesterone metabo-
lites; nonetheless, metabolic inactivation of proges-
terone to pregnanediol (5-pregnane-3,20-diol) is
Testosterone •> Estradiol
accomplished by the liver (MacDonald etal,
Androstenedione •* Estrone 1991) (see Figure 4).
16-Ketoestrone

16a-Hydroxyestrone Pregnenolone

Estriol Progesterone

Dihydroprogesterone Deoxycorticosterone

FIGURE 3. Biosynthesis and metabolism of estra- Pregnanolone

diol.
Pregnanediol

The biological activities of estrogens in FIGURE 4. Biosynthesis and metabolism of proges-

women include: (1) development, growth, and terone.
maintenance of secondary sex characteristics; (2)
uterine growth; (3) pulsatile release of luteinizing
hormone (LH) from the central nervous system; The biologic activities of progestins are prin-
(4) thickening of the vaginal mucosa; and (5) cipally observed during the luteal phase of the
ductal development in the breast. In the male, the menstrual cycle and pregnancy. Progesterone is
physiological significance of estrogens is largely necessary for glandular endometrial development
unknown but may be involved in the regulation of prior to nidation, development of mammary lob-
plasma androgen and estrogen levels as well as ules and alveoli as well as the maintenance of
sexual behavior (Mawhinney and Neubauer, pregnancy (i.e., endometrial gland function, de-
1979). creased excitability of myometrium and possible
effects on the immune system to decrease rejec-
tion of the developing fetus). Progesterone also
C. Progestins decreases hepatic secretion of VLDL and HDL,
diminishes insulin action, stimulates the hypotha-
The natural progestins, or steroids that have lamic respiratory center, elevates basal core body
progestational activity, are derived from a 21-car- temperature at ovulation, and enhances sodium
bon saturated steroid hydrocarbon known as excretion by the kidneys.
pregnane. Corticosteroids are also derived from
pregnane but differ from progestins because they III. MECHANISM OF ACTION OF SEX
contain an a-ketol group at C-17 and a ketone or STEROID HORMONES
hydroxy group at C-ll. The principal progesta-
tional hormone secreted into the bloodstream is In the bloodstream, sex steroid hormones exist
progesterone (pregn-4-ene-3,20-dione), which is in extremely low concentrations (in the femtomolar

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to nanomolar range) yet are capable of regulating cades, further insight into the actions of steroid
differentiation and growth in selected tissues dis- hormones has been gained and there have been
tant from the site of secretion. The actions of sex several comprehensive reviews on this subject
steroid hormones become even more intriguing (Hansen etal., 1988; Sheridan etal., 1988;
when one considers that the distinct biological Savouret, 1989; Martin et ai, 1990; Funder, 1991;
effects of these hormones depend on nominal O'Malley, 1991; Wilson, 1991). The current hy-
differences between relatively small (molecular pothesis of sex steroid hormone action (see Fig-
weight approximately 300 g) molecules. For ex- ure 5) begins with the secretion of the hormones
ample, testosterone, which is capable of powerful into the bloodstream, where they circulate, prin-
virilizing effects, differs from estradiol only by cipally bound (approximately 98%) to plasma
one carbon atom and four hydrogen atoms (see proteins. In the circulation, the unbound or free
Table 1). These apparently superficial differences hormone can enter the cell by diffusion and bind
in molecular structure of steroid hormones can to macromolecules called receptors. These large
alter the molecule's shape and qualitatively change intracellular protein receptors are located in both
biological activity. Specificity of hormone re- the cytoplasm and the nucleus of the cell. De-
sponse also depends on the presence of intracel- pending on the type of steroid hormone, the intra-
lular proteins called receptors, which specifically cellular localization of the receptor will vary.
recognize and selectively bind the hormone and Gonadal hormones principally reside in the nuclear
act in conceit with the hormone ligand to regulate component of target cells, but whether the native
gene expression. receptor is confined exclusively to the nucleus is
Initial observations in the 1960s that sex ste- an object of current research. When the steroid
roid hormones bind to intracellular proteins with hormone is bound to the receptor, it transforms
specificity and high affinity (Jensen etal., 1968; the receptor to an active configuration and the
Gorski etal., 1968) have led to the predominant activated receptor-steroid hormone complex binds
theory that steroid hormones act via receptors to with high affinity to specific nuclear sites (e.g.,
initiate biological responses. In the past 3 de- discrete DNA sequences, the nuclear matrix, non-

Cell Membrane Nuclear Membrane

3 p r « - mRNA

FIGURE 5. Mechanism of action of steroid hormones. The free steroid hormone (S) diffuses across the cell
membrane and binds to a cytosolic or nuclear receptor. Once bound the receptor is activated and binds to a nuclear
acceptor site where transcription of RNA occurs. (Reproduced with permission from Clark era/., 1992.)

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31
histone proteins, and the nuclear membrane). The C-terminus is a remarkably conserved area that
activation step of this process may occur in the contains the DNA binding domain. The hydro-
cytoplasm or the nucleus. Once the receptor-hor- philic D region is not conserved in length or
mone complex is bound to nuclear regulatory sequence but may serve as a hinge between the
elements, gene activation and transcription of hormone- and DNA-binding domains. The E/F
messenger RNA occurs. Following the nuclear regions located at the C-terminal are similar in
interaction, the receptor-hormone complex disas- size (250 to 300 amino acids), have moderate
sociates, leaving an unoccupied receptor and the amino acid homology among the different steroid
steroid hormone. The dissociated receptor is receptor proteins, and contain the hormone-bind-
thought to be in an inactive configuration that ing domain. Areas in both the N- and C-terminal
requires conversion to a form that can bind the are responsible for the transcriptional activation
steroid again and the steroid hormone is metabo- of the DNA (Gronemeyer etal, 1987; Kumar
lized and eliminated from the cell. The steps of etal, 1987).
dissociation and receptor recycling are poorly From these six regions, two important bind-
understood at this time. ing domains are present for sex steroid hormone
Although the regulation of gene transcription receptors. In one binding domain, the functional
by hormone-receptor complexes in the nucleus activation of the receptor is dependent on a dis-
appears to be the major biological action of sex tinct, high-affinity binding site for a specific
steroid hormones, these molecules also have other hormone. This steroid hormone binding domain
behaviors that are independent of the genome. is a large hydrophobic region located near the
Recent studies have shown that androgens, estro- C-terminal. It has been suggested that the ter-
gens, and progestins have membrane effects and tiary structure of receptor proteins forms a hy-
can influence the production of second messenger drophobic pocket that recognizes areas on both
systems. Sex steroid hormones can affect neural the A and D rings of the cyclopentano-
transmission (Ke and Ramirez, 1990; Lan et al, perhydrophenanthrene ring system. Early mod-
1990), modify the transport of calcium ions into els of steroid hormone action proposed that the
cells (Blackmore etal, 1990), and stimulate the hormone-induced allosteric changes in the re-
intracellular concentration of polyamines (Koenig ceptor influenced activation (O'Malley and
etal, 1989). Buller, 1977); however, recent models of recep-
tor activation have suggested that the hormone
dissociates an inhibitory protein, such as heat-
A. Steroid Hormone Receptor Structure shock protein 90, from the receptor (Catelli et al,
1985; Sanchez etal, 1985).
The receptors for steroid hormones are able The other receptor binding domain recognizes
to initiate a wide assortment of responses but are specific sites on DNA. This DNA-binding do-
very similar to one another, not only in their main of the steroid receptor is a highly conserved
mechanism of action but also in their structure area that contains a tetrahedral arrangement of
(Giguere etal, 1987; Evans, 1988). Generally, four cysteine residues around a zinc ion to form a
steroid hormone receptors consist of asymmetric zinc finger-like structure (Miller et al, 1985). Zinc
protein subunits with long (10:1) axial ratios. These fingers are an organization of amino acids where
subunits, which form either dimers or tetramers at zinc plays an important function in determining
low ionic strengths, range in weight from 80 to an arrangement that can bind specific sequences
100 kDa. As a class of regulatory proteins, the of DNA. In estrogen receptors, two zinc finger-
different steroid hormone receptors have a high like modules, separated by 14 to 17 amino acids,
degree of homology. Each protein can be divided are responsible for the binding of the receptor to
into six sections designated as regions A through specific DNA sequences (Hollenberg and Evans,
F (Krust et al, 1986). The A/B regions located at 1988) (see Figure 6). It appears that both fingers
the N-terminal are exceedingly variable in size are necessary for DNA binding; however, amino
(50 to over 500 amino acids) and have negligible acids found in the proximal portion (P box) of the
amino acid similarities among the different recep- first finger and the distal portion (D box) of the
tors. The C region located between the N- and second finger are crucial for determining the speci-

32
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 FINGER-LIKE UNIT FINGER-LIKE UNIT

v
R-Y ®-®-F-F-K-R-S-l-Q-G-H-N-D-Y-M^ "R-L - R - K - C - Y - E-V

FIGURE 6. Estrogen receptor zinc finger-like units. The estrogen receptor contains two amino acid domains that
independently fold around a zinc ion (Zn), forming a unique structure. The amino acids thought to interact with DNA
bases are located in the proximal box (O) and the amino acids thought to stabilize the receptor are located in the
distal box ([]).

ficity of binding (see Table 2). Green et al (1988) otide spacer (see Table 3). Once bound to a dis-
have suggested that the N-terminal zinc finger- tinct DNA sequence, the hormone-receptor com-
like domain determines target gene specificity, plex will regulate specific transcriptional events.
while the C-terminal zinc finger-like domain acts The elements responsible for the regulation of
to stabilize the interaction between receptor and transcription are not isolated to a single piece of
DNA. DNA but are arranged in complex chromatin struc-
tures. For gene activation, steroid receptors prob-
ably must interact with transcriptional factors and/
TABLE 2 or with components in the chromatin structure.
Sex Steroid Hormone DNA-Binding The exact nature of the interactions between ste-
Domains roid-hormone receptors and the constituent pro-
teins in the nucleus responsible for gene activation
Receptors PBox D Box
is only beginning to be elucidated.
Androgen GSCKV ASRND
Estrogen EGCKA PATNQ IV. THE PERIODONTIUM AS A TARGET
Progesterone GSCKV AGRND TISSUE FOR SEX STEROID HORMONES
Note. The amino acid sequence of the
DNA-binding domains found in the
The homeostasis of the periodontium is a
proximal box (P box) of the first complex, multifactorial relationship that involves,
finger-like region and the distal box
(D Box) of the second finger-like TABLE 3
region are listed.
Sex Steroid Hormone Binding Sites on DNA

Receptors Steroid responsive elements

After activation of the receptor, the receptor-
steroid complex binds to a specific site on the Androgen GGTACA-N3-TGTTCT
DNA that is referred to as a steroid responsive Estrogen AGGTCA-N3-TGACCT
element (SRE). SREs are unique for each recep- Progesterone GGTACA-N3-TGTTCT
tor but have common nucleotide characteristics. Note: Steroid responsive elements contain two
In general, SREs for sex steroids contain two hexanucleotide sequences separated by a
hexanucleotide sequences separated by a trinucle- trinucleotide spacer.

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at least in part, the endocrine system. Evidence pubertal age individuals of both sexes, but data
has accrued to suggest that tissues of the were not available on the pubertal status of the
periodontium are modulated by androgens, estro- individuals (Parfitt, 1957; Sutcliffe, 1972; Hefti
gens, and progestins. Although all four tissues of et al, 1981). Sutcliffe (1972) examined 127 school
the periodontium are regulated by sex steroid age children in a 6-year longitudinal study and
hormones at one time or another, most of our found an abrupt and transitory increase in the
information about hormone actions and effects incidence of gingivitis without a change in plaque
involve the gingiva. For this reason, this review levels. The mean age at which girls and boys
focuses on the actions of androgens, estrogens, reached their maximum gingivitis experience was
and progestins in the gingiva. 12 years and 10 months and 13 years and 7 months,
respectively. In a cross-sectional study examining
7380 children, gingival inflammation increased at
A. Clinical Phenomena age 11 in both sexes (Hefti etal, 1971), while
plaque levels remained constant in all age groups
One piece of evidence implicating the gin- (personal communication from Dr. Hefti). In most
giva as a target tissue for sex steroid hormones longitudinal or cross-sectional studies, the data
deals with clinical phenomena described dur- strongly indicate that there is a short period of
ing periods of hormone fluctuations. These clini- time when children experience an exaggerated
cal observations have confirmed an increased gingival inflammatory response to plaque. The
prevalence of gingival diseases with fluctuat- crux of the reported relationship between the in-
ing sex steroid hormone levels, even when oral creased incidence of gingivitis and onset of pu-
hygiene remained unchanged. In large part, the berty has depended on the chronological age of
periodontal changes have been characterized in the cohort examined. However, it should be noted
females, because they have distinctive cycles that chronological age is a poor predictor of the
of sex steroid hormone secretion. Therefore, it onset of puberty, and these data should only be
is not surprising that the majority of clinical considered circumstantial evidence that puberty-
observations were derived from women at vari- induced increases of plasma sex steroid hormones
ous times in their life. affect gingival tissues.

1. Puberty 2. Menstrual Cycle

Epidemiological data have shown that gingi- Following menarche, there is a periodicity of
vitis in children is a ubiquitous condition (Sutcliffe, estrogen and progesterone secretion that is an
1972; Hefti, 1981; Cutress, 1986). It has been important component for continued ovulation until
hypothesized that the incidence and severity of the menopause. This rhythm of sex steroid hor-
gingivitis in childhood is influenced by plaque mone secretion over a 25- to 30-d period has
levels, dental caries, mouth breathing, crowding been described as the menstrual cycle (see Fig-
of the teeth, tooth eruption, and puberty. Puberty, ure 7). In humans, the menstrual cycle can be
the complex process of sexual maturation result- divided into a follicular or proliferative phase and
ing in an individual capable of reproduction, in- a luteal or secretory phase. During the follicular
duces changes in physical appearance and behavior phase, estrogen levels rise and prior to ovulation
that is the direct result of increases in sex steroid the preovulatory follicle significantly increases
hormones, primarily testosterone in males and estrogen secretion, initiating a luteinizing hor-
estradiol in females. The dramatic rise in steroid mone surge that stimulates progesterone secre-
hormone levels during puberty in both sexes was tion and ovulation. After ovulation, the luteal phase
believed to have a transient effect on the inflam- is marked by increased progesterone and estrogen
matory status of the gingiva (Marshall-Day, 1951); secretion. During the final days of the luteal phase,
however, data to support this concept has been if fertilization has not occurred, the plasma levels
fragmentary. Several studies have demonstrated of progesterone and estradiol decline because of
an increase in gingival inflammation in circum- the demise of the corpus luteum.

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 1500 100

1000 3
O 3
E 50 O
a 500

12 -8 -4 0 4 8 12
DAYS FROM LH PEAK

FIGURE 7. The pattern of circulating hormone levels in the human menstrual cycle.
The plasma concentrations of progesterone (o) and estradiol (•) are depicted in the
menstrual cycle. The follicular or proliferative phase occurs 12 d prior to the LH peak
(days -12 to 0), and the luteal or secretory phase occurs 12 d after the LH peak (days
0 to 12). The solid bars represent menstrual periods and the open bar represents the
time of implantation during the luteal phase. The arrow indicates the time of ovulation.
(Reproduced with permission from Yen, 1991a).

In general, the periodontium does not exhibit from gingival crevices but found no change in
clinically obvious changes during the menstrual gingival exudates during the menstrual cycle.
cycle. Nonetheless, two different clinical findings Perhaps Holm-Pedersen and Loe (1967) were
have been noted in the oral cavity. One observa- unable to verify changes in crevicular fluid flow
tion deals with the inflammatory changes that during the menstrual cycle for several reasons.
develop in gingival tissues of the cycling human First of all, they failed to verify ovulation on the
female (Klein, 1934; Muhlemann, 1948; Lindhe day samples were collected. It is well known that
and Attstrom 1967). In a very small percentage of the time at which humans ovulate varies and these
women, ulcerations of the oral mucosa, vesicular investigators may have missed the event since
lesions, and bleeding have been described several they relied only on a set date to collect samples
days before menstruation. Muhlemann (1948) from subjects. In addition, the subjects in the
clinically and histologically described a case of Holm-Pedersen and Loe study had very low lev-
"gingivitis intermenstrualis" where bright red els of gingival inflammation (approximately 94%
hemorrhagic lesions of the interdental papilla of sites scored had a GI = 0). In contrast, the
developed prior to the menses. The more com- cohort of patients examined by Lindhe and
mon inflammatory changes that develop in the Attstrom (1967) had a preexisting mild gingival
gingiva seem to involve less dramatic clinical inflammation. Therefore, manifestation of hor-
alterations in the gingiva. For example, during the monal influences in the gingiva of susceptible
menstrual cycle, gingival exudate, an indicator of individuals may depend on the simultaneous pres-
gingival inflammation, has been shown to in- ence of gingival inflammation. Finally, the tech-
crease during ovulation. Lindhe and Attstrom nique used by Holm-Pedersen and Loe (1967) to
(1967) described an increase in the production of collect gingival crevicular fluid has low sensitiv-
gingival exudate during ovulation, which returned ity in detecting hormone-induced changes in
to baseline during menses. In 88% of the subjects crevicular fluid (Lindhe et al, 1968a).
evaluated, there was at least a 20% increase in The other significant observation that has been
gingival crevicular fluid during ovulation. Holm- described during the menstrual cycle is the ap-
Pedersen and Loe (1967) also examined exudates pearance of aphthous ulcers. Whether aphthae

35
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develop as a result of hormonal changes during cycle suggest that there is a population of women
the menstrual cycle remains controversial. Sev- whose oral mucosa exhibits cyclic changes; how-
eral investigators have described specific popu- ever, what role, if any, sex steroid hormones
lations of women who develop aphthous ulcers play in aphthous ulcer formation is not under-
during the luteal phase of the menstrual cycle stood.
(Strauss, 1947; Ferguson etai, 1978). Dolby
(1968) examined 20 women suffering recurrent
oral aphthae and demonstrated maximal ulcer- 3. Oral Contraceptives
ation in the luteal period, but did not ascertain
whether these changes were statistically signifi- Oral contraceptive agents are one of the most
cant. In another study, 415 women were exam- widely utilized class of drugs. In the U. S., it has
ined by questionnaire and a significant incidence been estimated that approximately 10,000,000
of recurrent oral ulcerations was reported during women are currently using these agents (Murad
the menstrual period in regularly cycling women and Kuret, 1990). Current oral contraceptives
(Ferguson et al, 1984). In contrast to these stud- consist of low doses of estrogens (50 |ig/d) and/
ies, other investigators have been unable to dem- or progestins (1.5 mg/d); however, it should be
onstrate any influence of the menstrual cycle on noted that initial hormone contraceptive formula-
aphthous ulcer formation (Ship et al, 1961; Segal tions contained higher concentrations of sex ste-
et al, 1974). For example, in one 36-month pro- roid hormones and that early clinical studies
spective study, 104 student nurses were exam- examined gingival conditions in women using
ined for the incidence of aphthous lesions. Using these higher doses of estrogens and/or progestins
daily diaries to monitor the time of menses and (see Table 4).
the onset of aphthae, no association was found Numerous clinical studies have recorded gin-
between recurrent aphthous ulcers and the men- gival changes that develop as a result of the use of
strual cycle (Segal etai, 1974). If the preva- oral contraceptive agents. Several case reports
lence of hormonally sensitive aphthous ulcers in described gingival enlargement induced by oral
the population is low, the population of patients contraceptives in otherwise healthy females with
examined by Segal and colleagues (1974) may no history of gingival hypertrophy or hyperplasia
not have been sufficiently large to distinguish if (Lynn, 1967; Kaufman, 1969; Sperber, 1969). In
menstrual-related mucosal ulcers develop. An- all cases, the gingival overgrowth was reversed
ecdotal reports of individuals with aphthous ul- when oral contraceptive use was discontinued or
cer formation in the luteal phase of the menstrual the dosage reduced. In addition, various clinical

TABLE 4
Concentrations of Sex Steroid Hormones in Oral Contraceptives Reported in Case Reports
and Clinical Studies

Oral Contraceptive
Reference Type of Report Progestin Estrogen

El-Ashiry etai (1970) Clinical study 4 mg megestrol acetate 50 pig ethenyl estradiol
Kaufmann (1969) Case report 1 mg ethynodiol diacetate 100 [Jig mestranol
Knight and Wade (1974) Clinical study Steroid not reported Steroid not reported;
no dose reported no dose reported
Lindhe and Bjorn (1967) Clinical study 5 mg megestrol acetate 100 pg mestranol
components and concentrations of Gestadydral (produced by
Hoffman-La Roche & Co.) were not reported.
Lynn, (1967) Case report 30 mg daily of an oral contraceptive that contained both
norethindrone and mestranol.
Pankhurst etai. (1981) Clinical study Steroid not reported Steroid not reported;
between 0.15-4.0 mg between 20-50 pg
Sperber (1969) Case report 2 mg norethindrone 100 |jg mestranol

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studies have demonstrated that women using hor- significance in this study may be due to the de-
monal contraceptive drugs have a higher inci- gree of error involved in the manual measurement
dence of gingival inflammation in comparison to of attachment levels, because Knight and Wade
women who do not use these agents (Lindhe and (1974) used a modified method to measure at-
Bjorn, 1967; El-Ashiry etal, 1970; Pankhurst tachment loss to obtain "greater accuracy."
etai, 1981). The use of oral contraceptives has
also been associated with changes in periodontal
attachment level. Knight and Wade (1974) found 4. Pregnancy
a statistically significant loss of attachment in
women taking exogenous sex steroid hormones Some of the most remarkable endocrine alter-
for over 1 1/2 years despite no differences in ations accompany pregnancy. The increases in
gingival inflammation between oral contracep- sex steroid levels that begin prior to fertilization
tive users and nonusers. In contrast, Pankhurst during the luteal phase of the menstrual cycle
et al. (1981) detected no change in the periodon- continue once implantation of the embryo occurs
tal attachment level despite an increase in the and are maintained until parturition (see Figure 8).
prevalence of gingival inflammation in women For example, pregnant women near or at term
taking oral contraceptives when compared with produce large quantities of sex steroid hormones
controls. Although the Pankhurst etai (1981) (20 mg of estradiol, 80 mg of estriol, and 300 mg
study found no difference in attachment levels of progesterone) on a daily basis. This promi-
among the groups, a trend of increased attach- nent increase in plasma hormone levels over
ment loss was evident in women taking oral con- several months has a dramatic effect on the
traceptives. The failure to find statistical periodontium throughout pregnancy.

"1 ILM PEAK

PROGESTERONE

u.**'

H
ESTETROL

\~X PROGESTERONE

! ;•

•M

« • » » i ' i
WEEKS GESTATONAL AGE
WEEKS GESTAT1ONAL AGE

FIGURE 8. Circulating hormone levels during human pregnancy. The plasma concentrations of estrogens (right
panel) and progestins (left panel) from the beginning of the menstrual cycle (week 0), to fertilization (week 2), to
parturition (week 40) are illustrated for a typical woman. The human gestational period can be separated into
trimesters. In these figures the first, second, and third trimesters range approximately 2 to 15 weeks, 15 to 27 weeks,
and 27 to 40 weeks, respectively. (Reproduced with permission from Yen, 1991b.)

37
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 During pregnancy, the prevalence and se- The changes observed in the gingiva during
verity of gingivitis have been reported to be and after menopause are quite different from other
elevated (Loe and Silness, 1963; Loe 1965; times in a woman's life. There are no endogenous
Hugoson, 1971; Arafat, 1974). Loe and Silness hormone-induced increases in gingival inflam-
(1963) used a cross-sectional study to examine mation or size; instead, desquamations of gingi-
121 pregnant and 61 postpartum women for val epithelium have been commonly reported. The
changes in gingival inflammation. During preg- question has arisen as to whether gingival
nancy, 100% of women exhibited gingival in- vesiculobullous lesions, which develop in women
flammation when compared with postpartum after the climacteric, are a manifestation of one of
controls. The prevalence and severity of the several different vesiculobullous diseases, a vari-
gingival inflammation were significantly higher ant of a single vesicular dermatologic disorder, or
in the pregnant vs. the postpartum patients, even a distinct disease under hormone control.
though plaque scores remained the same be- Desquamative gingival diseases were de-
tween the two groups (Silness and Loe, 1963). scribed in the late nineteenth century by Tomes
Similar results were obtained in a longitudinal (Tomes and Tomes, 1894), who noticed "a singu-
study that examined 26 women during and fol- lar modification of chronic inflammation of gums,
lowing pregnancy (Hugoson, 1971). In addi- in which, instead of becoming thickened and ir-
tion to confirming that the severity of gingival regular on the surface, they seem rather to de-
inflammation was exacerbated throughout preg- crease in size, assuming a very smooth and
nancy and reduced following parturition, this polished surface and mottled aspect. The patients
investigation also demonstrated that the sever- suffering from this complaint for the most part
ity of gingival inflammation was correlated with seem to be poor, middle-aged women in whom
sex steroid hormone levels during pregnancy menstruation was becoming irregular or had alto-
and not with the amount of plaque. Further- gether ceased." Early investigators believed gin-
more, gingival probing depths are larger (Loe gival lesions that developed in postmenopausal
and Silness, 1963; Hugoson, 1971; Miyazaki women were primarily the result of a change in
etai, 1991), bleeding on probing or tooth- their hormonal status. However, in the mid-
brushing is increased (Arafat, 1974; Miyazaki twentieth century, McCarthy etal (1960) con-
etai, 1991), and gingival crevicular fluid is cluded, after a review of the literature and the
elevated (Hugoson, 1971) in pregnant females. study of 40 cases over 12 years, that chronic
Finally, women who are pregnant also exhibit a desquamative gingivitis was probably a manifes-
low prevalence (0.5 to 0.8%) of localized gin- tation of several diseases with multiple etiologies.
gival enlargements (Maier and Orban, 1949; If there are several different disease entities, the
Loe and Silness, 1963). These pregnancy-in- contribution(s) of sex steroid hormones in the
duced gingival overgrowths are reversed fol- initiation and progression of specific desquamative
lowing parturition (Ziskin and Nesse, 1947). lesions is (are) largely undefined.
Circumstantial clinical data are available to
suggest that sex steroid hormones may play a role
5. Menopause in some types of desquamative gingival lesions.
First of all, most patients with desquamative gin-
In contrast to pregnancy when hormone lev- gival lesions are middle-aged and approximately
els are significantly elevated, during menopause 80% are female (Nisengard and Rogers, 1987).
ovarian function is declining and there is a reduc- Second, some lesions such as benign mucous
tion in the production and secretion of sex steroid membrane pemphigoid (Shklar and McCarthy,
hormones. Since the average age of menopause is 1971; Silverman etal, 1986) and lichen planus
51 years (McKinlay etal., 1972), a high percent- (Kovesi and Banoczy, 1973; Silverman and
age of women will spend, on average, one third of Griffith, 1974) are reported to have a female sex
their lives with no ovarian function. In the next 2 predilection. Finally, exogenous estrogens have
decades, approximately 40 million women in the been used to successfully treat desquamative le-
U.S. will pass through menopause. sions (Richman and Abarbanel, 1943a,b; Ziskin

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and Zegarelli, 1945; van Minden, 1946). This tion of androgens, estrogens, and progestins have
final piece of evidence suggests that some lesions been observed in the periodontium. Exposure of
are estrogen-sensitive; however, the studies must murine gingiva to dilute concentrations (136 r|g/
be viewed cautiously because the investigators 100 g body weight) of tritiated estradiol in vivo
were not blinded, placebos were not used, and the results in the accumulation and retention of la-
types of lesions were not identified. beled estradiol similar to that seen in the uterus at
Similar to desquamative gingival lesions, the 1 and 4 h after subcutaneous injection (Formicola
association between periodontitis and postmeno- et al, 1970). Estrogen treatment for 7 d reduced
pausal osteoporosis is not well defined. The evi- the concentration of labeled estradiol in murine
dence that osteoporosis, following surgical or gingiva and uterus by 86.5 and 54.6%, respec-
natural menopause, may be involved with the loss tively (Formicola etal, 1970). In addition, auto-
of periodontal attachment is circumstantial. Al- radiographic studies have demonstrated nuclear
though the theories for the pathogenesis of localization of estradiol in human gingival epithe-
osteoporosis are diverse, it is known that estrogen lium (Vittek et al, 1982) as well as human (Vittek
deficiency is an important factor in bone loss etal, 1982) and primate (Aufdemorte and
(Richelson et al, 1984). In addition, positive cor- Sheridan, 1981) gingival fibroblast cells. Similar
relations between estrogens and bone density have to estrogens, nuclear localization of methyl-
been demonstrated (Johnston et al., 1985; trienolone (R1881), a synthetic androgen that binds
Steinberg etal, 1989). Considering these find- primarily to androgen receptors, in human gingi-
ings, it is not surprising that bone mass from val epithelial cells and fibroblasts has also been
edentulous mandibles has been shown to differ by confirmed using autoradiographic procedures
age and sex. Several cross-sectional studies have (Vittek etal, 1985). In contrast to estradiol and
demonstrated decreased bone mass and density methyltrienolone, autoradiographic localization of
(Kribbs, 1990; Moshchil' etal, 1991), as well as progesterone in gingival epithelial cells has not
reduced bone mineral content (von Wopwern, been demonstrated. Mohamed (1974) found no
1988) in edentulous mandibles of postmenopausal uptake of progesterone into gingival epithelium
females. A variety of studies have attempted to and only a slight accumulation in the cytoplasm
provide insight into the relationship of osteoporosis of gingival fibroblasts from sexually immature
to periodontitis, but the results of these studies rabbits. Using a radiolabeled synthetic progestin
have been equivocal (Groen et al, 1968; Phillips (3H-ORG 2058) in bilateral oophorectomized and
and Ashley, 1973; Ward and Manson, 1973; adrenalectomized primates that were pretreated
Manson, 1976; Baum, 1981; Daniell, 1983; Kribbs, for 3 d with estradiol benzoate (50 |ig/kg body
1990). To ascertain if osteoporosis is a risk factor weight), 3H-ORG2058 was observed in the nuclei
for periodontal attachment loss in postmenopausal of fibroblasts found in the lamina propria of the
women, well-designed, long-term longitudinal gingiva, whereas gingival epithelial nuclei did
investigations controlling for temporal period fol- not concentrate the radiolabeled progestin (Weaker
lowing the menopause, plaque levels, medica- etal, 1988).
tions used (e.g., hormones, etc.), age, race, and
social habits (e.g. smoking, drinking, etc.) are C. Sex Steroid Hormone Metabolism
needed.
The metabolism of sex steroid hormones in
B. Tissue Specificity of Localization target tissues will either degrade and inactivate
the hormone or alter the hormone and increase the
Steroid hormone receptors are not ubiquitous potency. The gingiva of man and animals con-
but are located in high concentrations in hor- tains the necessary enzymatic machinery to me-
mone-sensitive tissues termed target tissues. Cy- tabolize all sex steroid hormones by common
toplasmic and nuclear receptors that bind specific metabolic pathways. To begin, the conversion of
hormones lead to the preferential accumulation estrone to estradiol occurs in both healthy and
and retention of hormones in target tissues. In a chronically inflamed human gingiva (ElAttar and
variety of species, the accumulation and localiza- Hugoson, 1974a) and may represent a bio-

39
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activation process. Gingival slices, incubated with D. Sex Steroid Hormone Receptors
radiolabeled estrogens, were capable of metabo-
lizing estrone to estradiol. The mean rate of con- Target tissues for steroid hormones contain
version for estrone to estradiol was threefold higher proteins that specifically recognize, retain and
in inflamed vs. healthy gingival tissues. In either initiate the actions of hormones. In the perio-
inflamed or healthy gingival tissues, there was dontium, intracellular binding proteins have been
little or no detectable conversion of estradiol to partially characterized for estrogens (Vittek et al,
estrone. The enhanced metabolic conversion of 1982b; Musajo etal, 1984; Lewko and Ander-
estrone to estradiol has also been documented in son, 1986; Staffolani etal, 1989), androgens
inflamed canine gingiva (ElAttar and Hugoson, (Southern etal, 1978; Vittek etal, 1985), and
1974b). progesterone (Vittek etal, 1982a). The human
The metabolism of androgens has been re- gingival cytosol receptor for estrogen is a high-
ported in human and murine gingiva. In the adult affinity (Kd 340 jM), low-capacity (4.5 /mol/mg
male rate, radiolabeled testosterone incubated with protein), heat- and proteolytic enzyme-sensitive
gingiva and vestibular oral tissue was converted protein that exhibits steroid specificity of binding
primarily to 5a- and 5p-reduced steroids (Vittek to estradiol but not cortisol, progesterone, or tes-
etal, 1974). The administration of medroxy- tosterone (Vittek et al, 1982b). During periods of
progesterone acetate for 2 weeks caused a two- gingival inflammation, the number of gingival
fold increase in 5oc-reductase activity (Vittek et al, estrophiles is elevated by almost tenfold (Staffolani
1974). In human males and females, the conver- etal, 1989). Human gingiva also contains an
sion of androstenedione to testosterone (ElAttar, androgen cytosol receptor that binds with high-
1974; Vittek etal, 1979) as well as the conver- affinity (Kd 2.2 r|M) and low-capacity ( 190
sion of testosterone to various 5a- and 5P-re- /mol/mg protein) to a heat-sensitive protein that
duced steroids (ElAttar, 1974; Vittek et al, 1979; exhibits steroid specificity to DHT (the principal
Ojanotko et al, 1980) is characteristic of gingiva. mediator of androgen action in adult tissues) but
Similar to estrogen metabolism, inflamed human not to progesterone, dexamethasone, cortisol,
gingiva is much more efficient in converting androstenedione, or estradiol (Southern etal,
androstenedione to testosterone (ElAttar, 1974; 1978). Additional techniques using immunohis-
Vittek etal, 1979) and testosterone to 5a- and tochemical detection have identified androgen re-
5p-DHT (Vittek ef al, 1979). ceptors in the nuclei of basal gingival epithelial
Unlike the conversion of androgens and es- cells and gingival fibroblasts (Ojanotko-Harri
trogens to metabolically active forms in the gin- et al, 1992). Little is known about the progester-
giva, the metabolism of progesterone is principally one receptor in human gingiva except that proges-
to inactive metabolites; however, similar to an- terone recognizes a cytosolic protein (Vittek et al,
drogens and estrogens, progesterone metabolism 1982c); the specificity and affinity of the protein
is elevated in inflamed gingival tissue (ElAttar remain to be described. In contrast to humans,
et al, 1973; Ojanotko-Harri, 1985; Ojanotko-Harri progesterone receptors have been characterized
etal, 1991). In human gingiva, progesterone is in rabbit gingiva and exhibit high-affinity (Kd
metabolized to a variety of metabolic products, 2.7 r\M), low-capacity ( 1 0 /mol/mg protein) bind-
and the principal metabolites include 20a-hy- ing to a heat- and proteolytic enzyme-sensitive
droxy-4-pregnen-3-one (ElAttar etal., 1973; protein that demonstrates a pattern of steroid speci-
Ojanotko-Harri, 1985), 5a-pregnane-3,20-dione ficity similar to progesterone receptors obtained
(ElAttar etal, 1973; Ojanotko-Harri, 1985), from other target tissues (Vittek etal, 1982a).
3P-hydroxy-5a-pregnane-20-one (Ojanotko-
Harri, 1985), 20a-hydroxy-5a-pregnan-3-one V. ETIOLOGIES OF PERIODONTAL
(Ojanotko-Harri, 1985), and some other "more ENDOCRINOPATHIES
polar" metabolites (Ojanotko-Harri, 1985). Of
the major metabolites, only 20a-hydroxy-4- A great deal of evidence has accumulated to
pregnen-3-one retains any progestational activ- implicate the periodontium as a target tissue for
ity (Ojanotko-Harri, 1985). steroid hormones; nonetheless, the specific rela-

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tionship of sex steroid hormones to periodontal cause of a single mechanism but rather multifac-
endocrinopathies remains an enigma. The role of torial in nature; nevertheless, each theory of how
gonadal hormones in periodontal diseases is ob- sex steroid hormones induce disease in the
scure; however, several explanations have been periodontium is examined.
forwarded in an attempt to describe how andro-
gens, estrogens, and progestins affect tissues of
the periodontium. To date, the most prominent A. Hormones and Microbial Organisms
explanations used to describe hormone action in
the periodontium have dealt with hormone effects Gingivitis is considered to be primarily a
on microbial organisms, the vasculature, the im- microbial disease that can be modulated by differ-
mune system, and specific cells in the perio- ent systemic and environmental factors (Stamm,
dontium (see Table 5). To be sure, the response of 1986). Therefore, it was natural to assume that
the periodontium in disease is probably not be- exacerbations in gingival inflammation observed

TABLE 5
Summary of Potential Etiologies for Gingival Endocrinopathies

References Proposed mechanism Comments

Delaneyefa/. (1986) Increased prevalence of gingivitis at puberty Changes in microbiota were not
Wojcicki efa/(1987) is due to elevated levels of specific bacteria correlated with changes in hormone
status; Yanover and Ellen (1986),
found no change in oral flora in a
longitudinal study of human
females at puberty
Kornman and Loesche (1980) Increased incidence of gingivitis during pregnancy Longitudinal study of 22 pregnant
Kornman and Loesche (1982) is due to an increase in Provetella intermedia; women found increases in
estradiol and progesterone accumulated by Provetella intermedia only during
P. intermedia and used as a substitute the second trimester; may be a
for vitamin K nonspecific accumulation of
estrogen and progesterone by
P. intermedia] only
pharmacologic concentrations of
sex steroid hormones are effective
as a substitute for vitamin K;
Jonsson etal. (1988) observed no
changes in oral flora in
pregnant women.
Lindhe and Branemark Increased incidence of gingivitis in women using Only pharmacologic concentrations
(1967a, b, c) oral contraceptives is due to reduction in of sex steroid hormones were
corpuscular flow rate, increased vascular effective; examined in hamster
permeability, and vascular proliferation in cheek pouch or depilated ear of
gingiva rabbit
Raber-Durlacher et at. (1992) Increased incidence of gingivitis during Evidence to support theory that
pregnancy is due to elevated levels of pregnancy gingivitis may be a
CD1,CD3, and CD4 cells consequence of reduced immuno-
responsiveness, resulting from
directed cytotoxicity against B cells
and macrophages by a subset of
helper T cells, is highly speculative.
Fukuda(1971) Changes in gingival phenotype Evidence to support dynamic
Kofoed(1971) (i.e., gingival enlargement, epithelial reciprocity of periodontium
Nicolau etal. (1979) desquamation etc.) are due to the is limited, particularly in respect
Mariotti etal. (1990) stimulation of specific populations of to the actions of sex steroid
Mariotti (1991) fibroblasts and epithelial cells by sex hormones
steroid hormones; secretion of hormone-
stimulated extracellular matrix
components has a permissive or
instructive effect on cells of gingiva

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during increases in plasma sex steroid hormones gressing normally through puberty and cross-sec-
were due to hormone-induced alterations in the tional changes in 9 subjects with precocious pu-
microbial flora of the gingival sulcus. Unfortu- berty. They found that P. intermedia was not
nately, data to support a transient increase in a correlated with physical maturation in either group.
specific microorganism during puberty or preg- Furthermore, plasma estradiol levels were not
nancy have been equivocal, and in some cases the correlated with the levels of black-pigmenting
speculative interpretation of specific results may bacteria.
have been overzealous. Additional controversy exists as to whether
Several investigators have described a tran- subgingival bacterial flora is influenced in women
sient increase in black-pigmented, Gram-nega- during pregnancy. In a cross-sectional study,
tive obligate anaerobic rods in children during Jonsson et al (1988) found no difference in lev-
puberty. Using three indicators of sexual matura- els of P. intermedia at any time during pregnancy
tion (menarche, breast development and pubic or between pregnant and nonpregnant control sub-
hair development), Delaney et al. (1986) grouped jects. In contrast, a longitudinal study of 22 women
22 girls into four stages of pre- and/or postmenarchal examined several species of bacteria during all
development and examined the changes in the per- three trimesters and found a significant increase
centage of Actinomyces sp. (A. naeslundii, A. vis- in the percentage of total colony-forming units for
cosus, A. odontolyticus), Actinobacillus actin- P. intermedia but only during the second trimes-
omycetemcomitans, total surface-translocating ter (21 to 24 weeks) (Kornman and Loesche, 1980).
bacteria (Capnocytophaga, Wolinella, and Eikenella In addition, gingival plaque samples from preg-
sp.), Fusobacterium nucleatum, spirochetes and nant patients in the second trimester were re-
black-pigmenting bacteria {Prevotella intermedia, ported to accumulate significantly more estradiol
Bacteroides melaninogenicus, Bacteroides and progesterone than plaque samples from other
denticola, Porphyromonas gingivalis) during these time periods. To explain these results, a later
periods of time. Unfortunately, the data provided study demonstrated that both estradiol and proges-
were a composite of the four groups examined; terone were selectively accumulated by P. inter-
nonetheless, the authors did state that black-pig- media and both ovarian hormones could be used
mented bacteria "in the predominant cultivable by P. intermedia as a substitute for vitamin K;
microbiota of the subgingival plaque in the 22 therefore, progesterone and/or estrogens could
subjects were related to only one developmental foster the growth of this microorganism (Kornman
assessment, that of menarchal stage, or composite and Loesche, 1982). Although the data suggest
sexual maturation (Kruskall-Wallis: p <0.05)'\ that P. intermedia increased during the second
Wojcicki et al. (1987), using bone age to confirm trimester as a result of elevated ovarian hormone
puberty, grouped 21 girls and 21 boys into three levels (Kornman and Loesche, 1980), the increase
stages (prepubertal, pubertal, and postpubertal) of P. intermedia during the second trimester of
and examined Fubosbacterium sp., total black- pregnancy may be independent of estrogens or
pigmented bacteria and Prevotella intermedia, progesterone and occur for other reasons. There
Bacteroides melanogenicus, and Bacteroides are several interesting observations relating to
denticolalBacteroides loeschii in each stage. In why P. intermedia may not be dependent on ova-
contrast to Delaney et al (1986), they found that rian hormones. The first observation deals with
the increase in black-pigmenting bacteria at pu- the transient increase of P. intermedia during the
berty was not reversed in postpubertal subjects; second trimester followed by the decline of this
however, a significant increase in P. intermedia microorganism to postpartum control values dur-
did occur and only in subjects judged to be in ing the third trimester, despite elevated hormone
puberty. Neither study examined the changes in levels (see Figure 8). If bacterial growth was de-
hormone status of the children as changes in the pendent on sex steroid hormones, then increases
microbiota developed. Contrary to the previous that develop in the second trimester would also be
two studies, Yanover and Ellen (1986) were un- evident in the third trimester and would decrease
able to find any changes in oral flora during pu- following parturition as do plasma hormone lev-
berty. Their study evaluated longitudinal changes els. Further, the accumulation of estradiol and
in black-pigmenting bacteria in 18 subjects pro- progesterone in second trimester plaque samples

42
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or pure cultures of P. intermedia may be a non- decreasing and progesterone levels are elevated
specific accumulation. Since competitive inhibi- (Prill and Gotz, 1961).
tion with other steroid-like molecules was not Although evidence exists for estrogen-induced
examined, it is unknown if the accumulation of changes of vascular function, how the responses
estradiol or progesterone was steroid specific or are mediated remain obscure. Several putative
purely dependent on the lipophilic nature of the mechanisms by which estrogens may control blood
plaque sample. Finally, if certain bacteria can use vessel tone include inhibiting movement of cal-
sex steroid hormones as a substitute for vitamin cium ions through the potential sensitive calcium
K, these bacteria should be able to convert to channels of uterine arteries after metabolic con-
estradiol or progesterone at physiologic concen- version to catechol estrogens (Stice et al, 1987),
trations. This does not appear to be the case be- influencing release (Bengtsson, 1978), or disposi-
cause the concentrations of estradiol and tion (Hamlet etal, 1980) of sympathetic trans-
progesterone used as a substitute for menadione, mitter, or affecting alpha adrenoceptor number or
a vitamin K analog, were pharmacologic (micro- affinity (Hoffman etal, 1981; Culocci etal.,
molar concentrations) in nature and may not rep- 1982). Estrogens may increase capillary perme-
resent what is seen in physiologic situations, such ability by stimulating the release of various me-
as in pregnancy. diators (e.g., adenosine, bradykinin, vasoactive
Whether the increases in plasma estrogen and intestinal polypeptide, neurotensin, Substance P,
progesterone during puberty or pregnancy stimu- various prostaglandins, AMP, ADP, ATP, cAMP,
late specific bacterial species remain inconclu- guanosine, thymidine, histamine, cytidine, uri-
sive. The current data indicate that P. intermedia dine, acetylcholine, isoproterenol, and glycosami-
may be elevated during pregnancy and around the noglycans); however, none of these mediators have
period of puberty. Nevertheless, whether this bac- been able to mimic the qualitative and quantita-
terial species is responsible for the observed gin- tive changes in blood flow induced by estrogen
gival inflammation during puberty and pregnancy (Magness and Rosenfeld, 1992). In contrast to the
and is increased as a result of increasing steroid principal effects induced by estrogen on blood
hormone concentrations remain to be determined. vessels, progesterone may have little or no direct
effect on the vasculature (Magness and Rosenfeld,
1992). Progesterone has been reported to antago-
B. Hormones and the Gingival nize the actions of estrogen, presumably by re-
Vasculature ducing estrogen receptor numbers (Magness and
Rosenfeld, 1992). In males, testosterone, which
In both intact and hormone-treated castrate can be metabolized to estradiol, will cause a sharp,
animals, one of the early responses of gonadal transient dilation of arterioles and venules in sex
hormones in accessory reproductive tissues accessory organs (Knisely etal., 1957).
involves increased blood volume, flow rate, The gingival vasculature also appears sensi-
hyperemia, and enlarged microvascular surface tive to sex steroid hormones. Several clinical stud-
(Spanziani, 1975). In females, estrogen, in physi- ies have correlated elevated gingival crevicular
ologic concentrations, is the principal sex steroid fluid with the presence of sex steroid hormones.
hormone responsible for alterations in blood ves- Because the net flow of gingival crevicular fluid
sels. For example, in the uterus estrogen will is related to an increase in the permeability of
stimulate blood flow (Kalman, 1958; Greiss and dentogingival blood vessels and the movement of
Gobble, 1970) and increase the movement of fluid interstitial fluid into the sulcus (Cimasoni, 1983),
and plasma proteins across blood vessel walls ovarian hormones may affect the integrity of the
within minutes of administration (Hechter et al., vasculature. In pregnant human females, gingival
1942; Friederici, 1967). During the human men- crevicular fluid is elevated by as much as 54%
strual cycle, endometrial blood flow increases when compared with gingival crevicular fluid
concomitantly with the rise in plasma estrogen levels from postpartum controls (Hugoson, 1971).
levels in the follicular phase; moreover, endome- Furthermore, exogenous estrogen and/or proges-
trial blood flow decreases during the luteal phase terone administration will significantly increase
of the menstrual cycle when estrogen levels are the amount of crevicular fluid in either inflamed

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or noninflamed canine dentitions (Lindhe etal, tion of 13:1 for systemic lupus erythematosus
1968a,b; Hugoson and Lindhe, 1971). (Inman, 1978) and 9:1 for Sjogren's Syndrome
Several studies have implied that ovarian (Whaley and Buchanan, 1980). Second, estrogens
hormones, particularly progesterone, were re- can also modulate many autoimmune diseases.
sponsible for a reduction in corpuscular flow For instance, rheumatoid arthritis (Hench, 1949),
rate (Lindhe and Branemark, 1967a), increased autoimmune thyroiditis (Amino etal., 1917a),
vascular permeability (Lindhe and Branemark, Graves disease (Amino etai, 1977b), poly-
1967b), and vascular proliferation (Lindhe and myositis/dermatomyositis (Gutierrez et ah, 1984),
Branemark, 1967c). However, the results of these systemic lupus erythematosus (Mund et ai, 1963),
studies must be placed in proper perspective and idiopathic thrombocytopenic purpura (Lorz
since pharmacologic doses of estrogens (up to and Frumin, 1961) are all affected during preg-
400,000,000 times the plasma concentration nancy. Third, sex steroid hormones have been
found in nonpregnant human females) and shown to modulate the production of cytokines,
progesterone (up to 1,000,000 times the plasma such as interleukin-6 (Tabibzadeh etaL, 1989).
concentration found in nonpregnant human fe- Finally, sex steroid receptors have been identified
males) were used to examine the effects of ova- on components of the immune system and may
rian hormones in nonperiodontal tissues such as act to modulate the actions of these cells (Ahmed,
the hamster cheek pouch and the ears of rabbits. 1988). For example, low concentrations of estra-
In a nonblinded, nonparametric, histological diol (1.5 r\M) have been shown to reduce poly-
study that used only progesterone, Mohamed morphonuclear leukocyte chemotaxis by as much
et al. (1974) described transient morphologic as 26.8% (Miyagi etai, 1992). In addition, a
changes leading to increased permeability in number of immune-sensitive cells, including CD1
rabbit gingival blood vessels. cells (primarily Langerhans cells) and CD3 cells
Estrogens are primarily responsible for vas- (majority of mature T lymphocytes) in the oral
cular changes in target tissues, such as the uterus, gingival epithelium as well as CD4 cells (helper
yet several studies have suggested that increased T cells) in the oral and sulcular gingival epithe-
vascular permeability in the gingiva is essentially lium were elevated during pregnancy (Raber-
the result of progesterone. As noted, these studies Durlacher^^/., 1993).
were principally descriptive in nature and/or used Observations concerning gender-related dis-
concentrations of hormones far higher than what ease susceptibility, hormone regulation of immune
is normally found in women. As in other target cells, and hormone modulation of autoimmune
tissues, the actions of estrogen and progesterone diseases offer initial evidence to support the
on the gingival vasculature are complex and yet premise that some immunologic reactions in the
to be defined. gingiva are probably affected by sex steroid hor-
mones. The type and degree of influence that sex
C. Hormones and the Immune System steroid hormones exert on the immune system in
the gingiva remain to be ascertained.
Immunological reactions play an important
role in the pathogenesis of periodontal diseases
(Genco, 1992) and our understanding of the rela- D. Hormones and Cells of the
tionship between sex steroid hormones and the Periodontium
immune system is developing rapidly. Although
it is not within the scope of this review to examine Sex steroid hormones exert considerable in-
the actions and interactions of steroid hormones fluence, both directly and indirectly, on cellular
with the immune system, there are several salient differentiation, proliferation, and growth in target
observations that suggest that changes in the tissues. In the oral cavity, androgens, estrogens
periodontium may develop as a result of the influ- and progestins are known to affect several cell
ence of sex steroid hormones on the immune types, and in the gingiva, reports dealing with the
system. First, there are a number of autoimmune actions of sex steroid hormones have focused
diseases that exhibit a gender-related susceptibil- primarily on two cell groups, the keratinocyte and
ity. For example, there is a female sex predilec- the fibroblast.

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 Many of the histologic studies that examined mesenchymal cells, mast cells, endothelial cells,
the effects of gonadal hormones on gingival epi- etc.) interspersed among a diverse number of
thelial cells were purely descriptive in manner macromolecules (Mariotti, 1993). The actions of
and the investigators were usually not blinded to sex steroid hormones on the extracellular matrix
the treatment modalities. Keeping this in mind, are a prime example of the dynamic response of
several investigators perceived that estrogens in- cells in gingival connective tissue during times of
creased epithelial keratinization and stimulated hormone fluctuations. Early studies examining
proliferation (Ziskin etal, 1936; Richman and the effects of sex steroid hormones on the gingi-
Abarbanel, 1943). Trott (1957) noticed a reduc- val extracellular matrix were primarily descrip-
tion in keratinization of marginal gingival epithe- tive in nature and ascribed histologic changes in
lium in postmenopausal women when plasma the composition of the entire tissue. For example,
estrogen levels were declining. In senile mice, initial histologic studies in humans described the
estrogens were reported to increase the down- maintenance of gingival connective tissue in
growth of epithelial attachment (Nutlay etal, women receiving exogenous estrogen (Ziskin and
1954). Beagrie (1966) described an estrogen-in- Zegarelli, 1945), whereas androgen treatment was
duced increase in thymidine uptake in murine oral effective in stimulating proliferation of connec-
epithelium and epithelial attachment; however, tive tissue elements in humans, castrate rhesus
no analysis was attempted to determine if these monkeys (Ziskin, 1941) and rats (Shklar etal,
differences were significant. In one of the few 1967). Later studies began to biochemically ana-
studies to quantify changes induced by estrogens lyze the changes that developed in the presence of
in epithelial cells, Litwack et al (1970) found the androgen or estrogen. A sexual dimorphism was
length of rete pegs, number of basal epithelial reported in the amount of gingival sialic acid
cells per area of basement membrane, and thymi- (Nicolau et al, 1979). Moreover, in young Wistar
dine labeling of epithelial cells in oral mucosa to rats, normal female gingiva was found to contain
be significantly increased after estrogen adminis- as much as 42% more N-acetylneuraminic acid in
tration to castrated adult female squirrel mon- comparison to age-matched males. Testosterone
keys. Moreover, estrogen also stimulated an was also found to have an effect on extracellular
increase in the number of basal epithelial cells per matrix components. Kofoed (1971) demonstrated
area of basement membrane in the gingiva of that gingival hyaluronic acid but not heparan sul-
squirrel monkeys. Similar to estrogens, the ac- fate, chondroitin-4-sulfate, chondroitin-6-sulfate,
tions of androgens and progestins on gingival or dermatan sulfate was androgen sensitive. More
epithelium are also ill-defined at the present time. specifically, castration of adult rats induced a 54%
In humans, simians, and rodents, androgens were reduction in hyaluronic acid that could be pre-
perceived to stimulate an increase in epithelial vented with subcutaneous injections of testoster-
cell number (Ziskin, 1941; Shklar et al, 1967). In one propionate. Investigations examining the effect
another study, the daily administration of of estrogen on collagen synthesis have been lim-
norethisterone acetate, a progestin, to nine healthy ited in the gingiva. Dyer etal (1980) found no
women between day 3 to 27 of the menstrual significant effect of a single dose of estrogen on
cycle, resulted in a significant reduction in the hydroxyproline-specific radioactivity in gingival
keratinization index and karyopyknotic index from or palatal tissues of ovariectomized, nulliparous
gingival smears (Klinger etal, 1981). The au- rats. Although the amount of newly synthesized
thors suggest that the reduction in gingival prolif- gingival collagen was not statistically different
eration was not due to the direct effects of the between estrogen-treated castrate and castrate
progestin but rather to a reduction of plasma es- control animals, differences between these two
tradiol induced by daily progesterone administra- groups may be masked either by the amount of
tion. Circumstantial evidence exists that sex steroid error around the means or because these experi-
hormones have an effect on gingival epithelium, ments allowed for a castration-induced regression
but the responses of keratinocytes to sex steroid prior to estrogen treatment. Evidence from vari-
hormones remain both obscure and complex. ous epithelial cell lines and tissues show that
The extracellular matrix of the periodontium hormone-sensitive cells fail to respond or have
is an intricate mosaic of cells (e.g., fibroblasts, diminished sensitivity to steroid hormones after a

45
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time period of reduced hormone secretion. Inves- that 20 |ig/ml of progesterone induced a signifi-
tigations using human epithelial tumor cell lines cant reduction in DNA synthesis and 40 ng/ml of
have demonstrated a loss or reduction of estro- progesterone reduced protein synthesis by as much
gen-sensitive cell growth after estrogen depriva- as 50% (Willershausen et al, 1986). In contrast to
tion (Darbre and King, 1988; Daly and Darbre, testosterone and progesterone, estrogens appear
1990). In addition to epithelial cells, stromal com- to be stimulatory in nature in gingival fibroblast
ponents have been shown to lose sensitivity to cell cultures. Estradiol was capable of stimulating
estrogen after a period of hormone deprivation. proliferation of fibroblasts derived from either
Research into the maintenance and restoration of feline or human drug-enlarged gingiva (Fukuda,
estrogen action has demonstrated that estradiol- 1971). In a study examining fibroblasts derived
induced increases in extracellular matrix compo- from clinically healthy human gingiva of pre-
nents are lost after a castration-induced regression menopausal women, physiological concentrations
(Mariotti and Mawhinney, 1982). of estradiol were found to stimulate cell prolifera-
The fibroblast is the principal cell type found tion in vitro (Mariotti, 1991). More specifically,
in the extracellular matrix of the gingiva gingival fibroblasts derived from the papilla of
(Narayanan and Page, 1983) and contemporary young, medically healthy premenopausal women
research is demonstrating that gingival fibroblasts were seeded in culture plates at a low density
are affected by all three sex steroid hormones. (11 cells/mm2) in media (MEM) supplemented
Androgens have an inhibitory effect on fibroblast with 10% FBS. After 24 h, media were removed,
proliferation. Testosterone has been shown to sig- cells washed twice with serum-free MEM, and
nificantly reduce the proliferative rate of fibro- media replaced with MEM containing 1% char-
blasts derived from either phenytoin-enlarged coal-treated FBS. Charcoal treatment of serum
human or newborn feline gingiva in media supple- was used to remove any endogenous steroids.
mented with 10% fetal bovine serum (FBS) Upon quiescence, cells were incubated with con-
(Fukuda, 1971). Human gingival fibroblasts also centrations of estradiol ranging from 1 \\M to
metabolize testosterone to 5oc-DHT, 4-andro- 1 fM. It was found that 1 r\M estradiol stimulated
stenedione, and 5oc-androstanediols in cell culture cell proliferation significantly above control lev-
(Sooriyamoorthy et al, 1984). Additional studies els in premenopausal fibroblast strains. In fact,
using fibroblast monolayers or fibroblast cytosols estradiol stimulated cell proliferation anywhere
have shown a significant increase above controls from 50% to 310% above control values. Further
in the metabolism of testosterone to 5oc-DHT and studies characterizing fibroblasts from premeno-
4-androstenedione by fibroblasts derived from pausal women demonstrated distinctive cell popu-
either phenytoin-, nifedipine-, or cyclosporine- lations. A fluorescent-activated cell sorter
induced gingival tissues (Sooriyamoorthy etal, revealed two distinct premenopausal gingival fi-
1988; Sooriyamoorthy et al, 1990). At this time, broblast populations: one containing a fluores-
it is unclear whether the increase in androgen cent-labeled estrogen probe and the other
metabolism by fibroblasts derived from drug-in- population consisting of cells that did not accu-
duced gingival enlargements is because of the mulate the probe (Mariotti et al, 1990). An in-
inflamed nature of the donor tissue or the drug terpretation of these preliminary results suggests
involved in increasing tissue size. Similar to the that a subpopulation of estrogen-sensitive gingi-
actions of testosterone on gingival fibroblasts cul- val fibroblasts exist in premenopausal women.
tures, the effects of progesterone on human and Hence, estrogen-stimulated proliferation of hu-
feline gingival fibroblast cell cultures revealed an man premenopausal gingival fibroblasts result
inhibition of gingival fibroblast proliferation in the proliferation of a distinct population of
(Fukuda, 1971; Willershausen et al, 1986). estrogen-sensitive cells.
Progesterone has been shown to significantly re- There is evidence to suggest that gonadal
duce the proliferative rate of fibroblasts derived hormones mediate the actions of some gingival
from either phenytoin-enlarged human or new- fibroblasts and epithelial cells and therefore con-
born feline gingiva in media supplemented with tribute to the maintenance of this tissue. It is
10% FBS (Fukuda, 1971). A later study con- known that gingival tissues and/or cells metabo-
firmed these results in humans, demonstrating lize sex steroid hormones, contain hormone re-

46
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ceptors and proliferate in the presence of specific or by serving as an alternative growth factor for
steroids. Some of the hormonal changes that de- bacteria; however, it would be naive to think that
velop in cellular elements associated with inflam- the actions of these diverse biological molecules
matory periodontal diseases have been identified, are limited to these responses alone. Contempo-
including alterations in metabolism of sex steroid rary models for hormone action in the perio-
hormones (ElAttar etal., 1973; ElAttar, 1974; dontium will depend on understanding the actions
ElAttar and Hugoson, 1974a; Vittek etal, 1979; and interactions of different hormones with the
Ojantko-Harri, 1985; Ojantko-Harri etal, 1991) resident population of cells in a specific tissue
and the number of hormone receptors (Southern (see Table 5). For example, the secretion of soluble
et al, 1978; Vittek et a/., 1982b; Staffolani et al9 (i.e., growth factors, cytokines, etc.) and insoluble
1989). Despite the observed influence of sex ste- (i.e., extracellular matrix components) signals from
roid hormones on the gingiva, the specific effects estrogen-sensitive cells may dictate gingival phe-
of gonadal hormones on cellular function in this notype and the response of the gingiva to environ-
tissue remain to be elucidated. For example, the mental insults.
molecular mechanisms that steroid hormones use When one considers the primary functions of
to affect cell differentiation, proliferation, and sex steroid hormones, the periodontium would
growth remain ill-defined. Furthermore, it is un- appear to be an odd target; however, given the
known if gonadal hormones, such as estradiol, act influence of sex steroid hormones on perio-
directly on cells or whether other hormone-stimu- dontium, health and lifestyles of women are sig-
lated autocrine and paracrine growth factors, such nificantly impacted. Further, the prominent use of
as IGF-I, IGF-II, TGF-oo, TGF-p, EGF, and FGF exogenous hormones for contraception or hor-
(Dickson and Lippman, 1988; McCarty and mone replacement expands the importance of un-
McCarty, 1991) are responsible for modulating derstanding the actions of sex steroid hormones
cell function. in the periodontium. Future research must inves-
tigate the relationship of hormones to periodontal
diseases in pre- and postmenopausal women as
VI. SUMMARY well as the possibility of a sexual dimorphism of
hormone action. Throughout life in both sexes,
The assertion that hormone-sensitive peri- the association between estrogens, progestins, and
odontal tissues exist relies on several salient ob- androgens and desquamative gingival diseases,
servations, including an increased incidence and inflammatory periodontal diseases, drug-induced
severity of periodontal diseases during periods of gingival overgrowths, maxillary and mandibular
hormone fluctuations, retention and metabolic osteoporosis, immunologic oral diseases, and oral
conversion of sex steroid hormones and the pres- neoplasms require further investigation. The ac-
ence of steroid hormone receptors in periodontal tions of androgens, estrogens, and progesterone
tissues. Much of the data examining hormone in tissues of the periodontium remain an enigma
behavior in the periodontium has focused on the in many ways; nonetheless, future investigations
actions of estrogens in the gingiva; unfortunately, into the actions of sex steroid hormones will pro-
less is known of the actions of androgens or vide an extraordinary understanding of periodon-
progestins in gingiva or the behavior of any sex tal endocrinology.
steroid hormone on the periodontal ligament,
cementum, or alveolar bone. Moreover, our cur- ACKNOWLEDGMENTS
rent knowledge of the specific actions of sex ste-
roid-hormones in the gingiva, periodontal This manuscript was supported by NIDR grant
ligament, cementum, or alveolar bone is quite DEO9121.
limited.
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